The Journal of Experimental Medicine
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Published online 16 July 2001. doi:10.1084/jem.194.2.143
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© The Rockefeller University Press, 0022-1007/2001/7/143/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 2, July 16, 2001 143-154

Original Article

Regulation of Interleukin (IL)-18 Receptor {alpha} Chain Expression on CD4+ T Cells during T Helper (Th)1/Th2 Differentiation: Critical Downregulatory Role of IL-4

Ronald B. Smeltza, June Chena,b, Jane Hu-Lia, and Ethan M. Shevacha
a Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
b Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program, Bethesda, MD 20814

Correspondence to: Ethan M. Shevach, National Institutes of Health, Bldg. 10, Rm. 11N315, Bethesda, MD 20892. Tel:301-496-6449 Fax:301-496-0222 E-mail:ems1{at}mail.nih.gov.

Interleukin (IL)-18 has been well characterized as a costimulatory factor for the induction of IL-12–mediated interferon (IFN)-{gamma} production by T helper (Th)1 cells, but also can induce IL-4 production and thus facilitate the differentiation of Th2 cells. To determine the mechanisms by which IL-18 might regulate these diametrically distinct immune responses, we have analyzed the role of cytokines in the regulation of IL-18 receptor {alpha} chain (IL-18R{alpha}) expression. The majority of peripheral CD4+ T cells constitutively expressed the IL-18R{alpha}. Upon antigen stimulation in the presence of IL-12, marked enhancement of IL-18R{alpha} expression was observed. IL-12–mediated upregulation of IL-18R{alpha} required IFN-{gamma}. Activated CD4+ T cells that expressed low levels of IL-18R{alpha} could produce IFN-{gamma} when stimulated with the combination of IL-12 and IL-18, while CD4+ cells which expressed high levels of IL-18R{alpha} could respond to IL-18 alone. In contrast, T cell stimulation in the presence of IL-4 resulted in a downregulation of IL-18R{alpha} expression. Both IL-4-/- and signal transducer and activator of transcription (Stat)6-/- T cells expressed higher levels of IL-18R{alpha} after TCR stimulation. Furthermore, activated T cells from Stat6-/- mice produced more IFN-{gamma} in response to IL-18 than wild-type controls. Thus, positive/negative regulation of the IL-18R{alpha} by the major inductive cytokines (IL-12 and IL-4) determines the capacity of IL-18 to polarize an immune response.

Key Words: IFN-{gamma}–inducing factor, IL-12, IL-1R–related protein, Stat, IFN-{gamma}


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